Psoriasis affects 2% of the world's population. Very recently, it was appreciated that psoriasis has many features of an autoimmune disease, and a pathogenic paradigm that implicates activated skin homing T cells responding to an as yet unknown epidermal antigen(s) has emerged. In support of this paradigm, it is clear that all effective treatments for psoriasis have T cells as their targets. Skin directed therapies, including UVB and PUVA, directly induce apoptosis of intraepidermal T cells, while systemic therapies such as low dose methotrexate and cyclosporin target activated T cells throughout the body. More recently, a number of clinical trials have been initiated that use novel immunomodulatory agents such as CTLAIg, DAB-IL-2, anti-CD40L, and LFA3-TIP. Because the prominent immunological component of psoriasis was only recently appreciated there are large gaps in our knowledge about the immunopathology of this disease. In this proposal, we hypothesize that psoriasis is mediated by a recirculating population of CD8+, CLA (cutaneous, lymphocyte antigen) + effector T cells that become activated in epidermis in response to autoantigen. In aim 1, we propose to compare the VbetaCDR3 spectratype profile of lesional psoriatic CD8+ (CD25+) T cells with the analogous profile found in the CLA+ CD8+ fraction of peripheral blood. It is predicted that substantial overlap will exist. In aim 2, using epidermal antigen as well as anti-CD3, we will isolate and expand clones of putative disease related (as well as unrelated) CD8+ T cells form both blood and epidermis. In our third aim, we will use an established SCID/Hu model, involving non-lesional psoriatic skin grafted onto SCID mice, to test whether putative disease related clones can induce a psoriatic phenotype in vivo. Using this model, we will also test the efficacy and mechanism of action of both anti CD40 ligand and LFA- 3TIP in treating psoriasis. Finally, in our fourth aim we will perform transcriptional profiling on T cells (including candidate disease related clones) and epidermal cells from psoriasis patients and from normal patients in an effort to carefully assess differences between these populations. The long term goal of this research is to better understand the nature of immune response underlying psoriasis. This will provide a means to understanding why certain therapeutic approaches are superior to others, as well as to developing novel approaches to therapy.